Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was a multicenter, randomized controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with rest transthoracic echocardiographic measurements, the predictive value of 8 Doppler echocardiographic measurements—left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic (mitral valve peak early diastolic/peak late diastolic [E/A] ratio, peak mitral valve early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity [E/E′] ratio, and deceleration time) function, left atrial dimension, and mitral regurgitation severity—was examined for a primary end point of all-cause death or hospitalization and a secondary end point of cardiovascular disease death or HF hospitalization. Also compared was the prognostic value of echocardiographic variables versus peak oxygen consumption (V o 2 ). Mitral valve E/A and E/E′ ratios were more powerful independent predictors of clinical end points than the LV ejection fraction but less powerful than peak V o 2 . In multivariate analyses for predicting the primary end point, adding E/A ratio to a basic demographic and clinical model increased the C-index from 0.61 to 0.62, compared with 0.64 after adding peak V o 2 . For the secondary end point, 6 echocardiographic variables, but not the LV ejection fraction or left atrial dimension, provided independent predictive power over the basic model. The addition of E/E′ or E/A to the basic model increased the C-index from 0.70 to 0.72 and 0.73, respectively (all p values <0.0001). Simultaneously adding E/A ratio and peak V o 2 to the basic model increased the C-index to 0.75 (p <0.0005). No echocardiographic variable was significantly related to the change from baseline to 3 months in exercise peak V o 2 . In conclusion, the addition of echocardiographic LV diastolic function variables improves the prognostic value of a basic demographic and clinical model for cardiovascular disease outcomes.
In the present analysis, we examined the prognostic power of baseline Doppler echocardiographic measures of left ventricular (LV) and left atrial (LA) anatomy, LV systolic and diastolic function, and mitral regurgitation (MR) for overall and cardiovascular disease (CVD)–related outcomes and 3-month exercise training effect in patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). The major hypothesis was increased LV mass, LV internal dimension, LA dimension, and MR severity, a decreased LV ejection fraction (LVEF), and decreased LV diastolic function, as measured at baseline by Doppler echocardiography, would (1) improve the prediction, over a basic model of demographic and clinical variables, of increased all-cause death or all-cause hospitalization (the primary end point), as well as CVD death or heart failure (HF) hospitalization (secondary end points), over a 30-month median follow-up period and (2) predict a poorer exercise training effect, as measured by the change from baseline to 3-months in exercise peak oxygen consumption (V o 2 ), in the exercise training intervention group.
Methods
The design, primary outcome, and baseline Doppler echocardiographic findings of the HF-ACTION study have been previously reported. Enrollment criteria included an LVEF ≤35%, New York Heart Association clinical class II to IV HF, and sufficient ability to undergo exercise training. Patients were excluded if they were unable to exercise, were already exercising regularly, or had experienced CVD events in the previous 6 weeks. Patients were treated optimally according to current practice guidelines. Overall, 2,331 patients were randomly assigned to either participate in 36 sessions of facility-based, followed by home-based, exercise training for the remainder of the trial, in addition to usual care, or to receive usual care alone; the median follow-up period was approximately 2.5 years.
Doppler echocardiography was performed at baseline using standard methods; echocardiographic recordings were forwarded to a core laboratory for analysis. Studies were read blinded as to demographic and clinical information by a primary reader and overread by an experienced level III echocardiographer using a measurement workstation (Digisonics, Inc., Houston, Texas). The following echocardiographic variables were measured or derived: LV mass, LV diastolic dimension, LV volumes, and the LVEF; LA dimension, peak mitral valve early diastolic (E) velocity, the average of septal and lateral myocardial annular tissue velocities (E′), the E/E′ ratio, the peak early diastolic/peak late diastolic (E/A) velocity ratio, early diastolic deceleration time, and MR grade. MR was graded from apical-view color Doppler echocardiographic images as follows: 0 = none, 1 = trace, 2 = mild, 3 = mild to moderate, 4 = moderate, 5 = moderately severe, and 6 = severe. LV dimensions, wall thickness, and mass and LA dimension were measured from 2-dimensionally derived M-mode echocardiograms. If M-mode echocardiograms were judged suboptimal, linear dimensions were measured from 2-dimensional images. Peak E and A mitral valve pulsed-Doppler velocities were measured at the mitral leaflet tip level during diastole in the apical 4-chamber view. Septal and lateral E′ myocardial velocities were recorded with sample volumes positioned within 1 cm of septal and lateral insertion sites, respectively, of the anterior and posterior mitral leaflets. Measures of decreased LV diastolic function included abnormal E/A ratio (<0.75 or >1.5), decreased early diastolic deceleration time, increased E/E′ ratio, and increased LA dimension.
Symptom-limited exercise testing with gas exchange measurement was completed using commercially available metabolic carts and motor-driven treadmills, using a modified Naughton protocol in 91% and cycle ergometers in 9% of subjects. Exercise test supervisors encouraged patients to exercise to exhaustion. The respiratory exchange ratio was used to confirm satisfactory exercise effort. Peak V o 2 was determined in a core laboratory as the highest oxygen consumption normalized to body mass (in milliliters per kilogram per minute) for a 15- or 20-second interval during the last 90 seconds of exercise or the first 30 seconds of recovery. The independent relations of baseline demographic and clinical variables to clinical outcomes were assessed using bootstrapped, step-down variable selection. Partially on the basis of this assessment, the following were included in models to determine the independent predictive ability of echocardiographic variables for primary or secondary CVD outcomes: age, gender, race, body surface area, geographic region, Kansas City Cardiomyopathy Questionnaire symptom stability score, blood urea nitrogen, ventricular conduction, β-blocker dose, and loop diuretic dose.
Univariate and multivariate Cox regression were used to analyze relations of demographic and clinical, Doppler echocardiographic, and exercise training (peak V o 2 ) variables to the primary and secondary outcomes. The bootstrap-corrected C-index was used to evaluate the predictive ability of multivariate models for the primary and secondary outcomes. In the exercise training group, univariate correlations between Doppler echocardiographic variables and change in peak V o 2 between baseline and 3 months of training were examined using linear regression analysis. Kaplan-Meier curves were used to display event rates. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina) and R Design Library version 2.9.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at a 2-tailed α level of 0.05, with no adjustment for multiple comparisons. Unless otherwise indicated, all p values are based on the likelihood ratio chi-square statistic.
Results
Table 1 lists selected demographic, clinical, and echocardiographic variables in the overall cohort (n = 2,331) and in the subgroup (n = 519) for whom complete data were available for the primary end point in multivariate models. Most patients in the cohort were men, white, and were in New York Heart Association clinical class II and class III HF. There were no qualitative differences in demographic (age, gender, body mass index, and race), exercise, and LVEF variables between the overall cohort and the echocardiographic subgroup. The largest source of missing data was related to E′ measurements being available in only 909 patients (see Table 2 ), because tissue velocity measurements were not routinely recorded at some centers.
| Parameter | Overall Cohort (n = 2,331) | Cohort With Complete Echocardiographic Data for Primary End Point (n = 519) |
|---|---|---|
| Age (years) | 59 (51–68) | 59 (50–68) |
| Men | 72% | 69% |
| Race | ||
| White | 62% | 59% |
| Black | 33% | 34% |
| Other | 5% | 7% |
| Body surface area (m 2 ) | 2.1 (1.9–2.3) | 2.1 (1.9–2.3) |
| Blood urea nitrogen (mg/dl) | 20 (15–28) | 20 (14–28) |
| Diabetes mellitus | 32% | 32% |
| LVEF (%) | 25 (20–30) | 25 (21–31) |
| New York Heart Association class | ||
| II | 63% | 65% |
| III | 36% | 35% |
| Peak V o 2 (ml/kg/min) | 14.4 (11.5–17.7) | 15.8 (11.8–17.8) |
| Ventricular conduction | ||
| Interventricular conduction delay | 13% | 13% |
| Left bundle branch block | 17% | 15% |
| Normal | 43% | 47% |
| Paced rhythm | 24% | 21% |
| Right bundle branch block | 4% | 4% |
| Echocardiographic Parameter | Sample Size | Hazard Ratio (95% Confidence Interval) | Chi-Square Value | p Value |
|---|---|---|---|---|
| LV diastolic dimension | 1,646 | 1.09 (1.04–1.15) | 12.3 | 0.0005 |
| LV mass (per 100 g) | 1,646 | 1.08 (1.04–1.12) | 13.5 | 0.0002 |
| LVEF (per 5%) | 2,327 | 0.89 (0.86–0.92) | 49.7 | <0.0001 |
| LA dimension | 1,646 | 1.30 (1.21–1.41) | 48.1 | <0.0001 |
| Peak mitral early diastolic/peak late diastolic velocity ratio | 1,550 | 1.15 (1.08–1.22) | 19.5 | <0.0001 |
| Early diastolic deceleration time | 1,604 | 0.91 (0.87–0.95) | 18.6 | <0.0001 |
| Tissue Doppler peak early diastolic myocardial velocity | 909 | 0.98 (0.96–1.00) | 6.4 | 0.01 |
| Peak mitral early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity ratio | 796 | 1.03 (1.01–1.04) | 18.7 | <0.0001 |
| MR grade (grades 0–4 vs 5 or 6) | 2,135 | 1.53 (1.31–1.77) | 27.8 | <0.0001 |
| Peak V o 2 | 2,275 | 0.92 (0.91–0.93) | 199.0 | <0.0001 |
Table 2 lists univariate predictors of the primary end point (all-cause hospitalization or all-cause death). Among the 2,331 HF-ACTION patients, measurements for LV diastolic dimension, LV mass, LA dimension, E/A ratio, and deceleration time were available for 1,550 to 1,646 patients. Tissue Doppler–based parameters, including E′ velocity and E/E′ velocity, were present in only 909 and 796 patients, respectively. Except for E′ velocity (barely significant), all echocardiographic variables were highly statistically significant univariate predictors of the primary end point; however, peak V o 2 was a better predictor than any echocardiographic variable.
Table 3 lists C-index and multivariate p values for the primary end point when each echocardiographic variable was separately added to the basic multivariate model (which included only 519 patients who had no missing data for all variables). Only E/A ratio increased (slightly) the C-index of the basic model (from 0.61 to 0.62, p = 0.003); nevertheless, the E/A and E/E′ ratios had highly significant chi-square p values. (A significant chi-square p value can indicate statistical improvement in model fit by the inclusion of a variable in the absence of substantive improvement in model discrimination between higher and lower risk patients, denoted by the C-index. ) The other 7 echocardiographic variables added little to prediction beyond that achieved by the basic multivariate model plus E/A ratio. Importantly, peak V o 2 improved risk discrimination independently of the basic model and echocardiographic variables, increasing the C-index from 0.62 to 0.64, while echocardiographic variables did not improve risk discrimination of the basic model plus peak V o 2 , with the C-index remaining unchanged at 0.64.
| Multivariate Model | Multivariate Model Chi-Square Value | Multivariate p Value of Added Predictor(s) Beyond the Basic Model | C-Index |
|---|---|---|---|
| Basic | 57.8 | 0.61 | |
| Basic + LV diastolic dimension | 58.4 | 0.49 | 0.61 |
| Basic + LV mass | 58.0 | 0.69 | 0.61 |
| Basic + LVEF | 58.1 | 0.60 | 0.61 |
| Basic + LA dimension | 61.1 | 0.07 | 0.61 |
| Basic + peak mitral early diastolic/peak late diastolic velocity ratio | 66.6 | 0.003 | 0.62 |
| Basic + early diastolic deceleration time | 60.2 | 0.12 | 0.61 |
| Basic + peak mitral early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity ratio | 65.6 | 0.005 | 0.61 |
| Basic + MR grade | 62.7 | 0.08 | 0.61 |
| Basic + all 8 echocardiographic variables | 74.6 | Multiple added predictors | 0.62 |
| Basic + peak V o 2 | 92.5 | <0.0001 | 0.64 |
| Basic + peak V o 2 + peak mitral early diastolic/peak late diastolic velocity ratio | 94.8 | 0.13 (E/A), <0.0001 (peak V o 2) | 0.64 |
Table 4 lists the univariate predictors for the secondary combined end point (CVD mortality or HF hospitalization). All echocardiographic variables, except for E′ velocity, were highly statistically significant predictors of the secondary end point. LA dimension, the LVEF, MR grade, E/A ratio, and E/E′ ratio were the most important echocardiographic predictors of the secondary end point, but peak V o 2 was even more important. Table 5 lists multivariate p values and C-indexes for the secondary end point when each of the 8 echocardiographic variables was separately added to the basic multivariate model. The multivariate models included only patients who had data for all variables. The E/A and E/E′ ratios were the most statistically significant echocardiographic variables; their addition to the basic model resulted in the most substantial increases in the C-index (from 0.70 for the basic model to 0.73 and 0.72, respectively). However, peak V o 2 was a stronger independent predictor for the secondary end point (C-index = 0.74) than any echocardiographic variable. Moreover, peak V o 2 was an independent predictor of outcomes even when all 8 echocardiographic variables were included. There was no difference in predictive ability between the basic model plus all 8 echocardiographic variables and peak V o 2 versus the basic model plus E/A ratio and peak V o 2 . In the 972 patients in the exercise training arm with serial measurements, no echocardiographic variable was significantly related to the change from baseline to 3 months in peak V o 2 .
| Echocardiographic Parameter | Sample Size | Hazard Ratio (95% Confidence Interval) | Chi-Square Value | p Value |
|---|---|---|---|---|
| LV diastolic dimension | 1,646 | 1.14 (1.06–1.23) | 12.7 | 0.0004 |
| LV mass (per 100 g) | 1,646 | 1.10 (1.04–1.17) | 10.8 | 0.001 |
| LVEF (per 5%) | 2,327 | 0.82 (0.78–0.87) | 58.3 | <0.0001 |
| LA dimension | 1,646 | 1.48 (1.33–1.65) | 49.7 | <0.0001 |
| Peak mitral early diastolic/peak late diastolic velocity ratio | 1,550 | 1.43 (1.33–1.54) | 71.2 | <0.0001 |
| Early diastolic deceleration time (per 50 ms) | 1,604 | 0.83 (0.77–0.89) | 27.9 | <0.0001 |
| Tissue Doppler peak early diastolic myocardial velocity | 909 | 0.98 (0.95–1.01) | 2.24 | 0.13 |
| Peak mitral early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity ratio | 796 | 1.23 (1.15–1.33) | 25.5 | <0.0001 |
| MR grade (grades 0–4 vs 5 or 6) | 2,135 | 2.3 (1.9–2.8) | 61.1 | <0.0001 |
| Peak V o 2 | 2,275 | 0.86 (0.85–0.88) | 255.3 | <0.0001 |
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